Uncovering Missing Heritability in Rare Diseases

Abstract

The problem of ‘missing heritability’ affects both common and rare diseases hindering: discovery, diagnosis, and patient care. The ‘missing heritability’ concept has been mainly associated with common and complex diseases where promising modern technological advances, like genome-wide association studies (GWAS), were unable to uncover the complete genetic mechanism of the disease/trait. Although rare diseases (RDs) have low prevalence individually, collectively they are common. Furthermore, multi-level genetic and phenotypic complexity when combined with the individual rarity of these conditions poses an important challenge in the quest to identify causative genetic changes in RD patients. In recent years, high throughput sequencing has accelerated discovery and diagnosis in RDs. However, despite the several-fold increase (from ~10% using traditional to ~40% using genome-wide genetic testing) in finding genetic causes of these diseases in RD patients, as is the case in common diseases—the majority of RDs are also facing the ‘missing heritability’ problem. This review outlines the key role of high throughput sequencing in uncovering genetics behind RDs, with a particular focus on genome sequencing. We review current advances and challenges of sequencing technologies, bioinformatics approaches, and resources.

Large scale in silico characterization of repeat expansion variation in human genomes

“…Variation in protein coding exons accounts for the majority of the known pathogenic changes causing rare monogenic disorders. As approximately 50% of the 7,000 clinically defined diseases remain genetically unexplained 1 , we and others have speculated that non-coding sequence variation is contributing more significantly to the pathogenic variant spectrum 2,3 . Structural variation is already shown to play an important role in non-coding regions of the genome 4 .…”

Genetic Modifiers and Rare Mendelian Disease

“…Phenotypic heterogeneity and variability is a major concern for rare Mendelian disorders, which often leads to misdiagnosis and/or delayed diagnosis [19,114,157,158]. However, naturally occurring suppressor modifiers that reduce the severity or rescue an individual from the adverse effect of a disease-causing mutation can guide researchers and clinicians to its potential therapeutics [8,117].…”

“…These modifiers may result in a different/novel phenotype. Disease characterization becomes even more challenging for individuals carrying two or more monogenic disorders that may have overlapping (resulting in blended) or different (resulting in composite) phenotypes each of which may be modifiable [7,19] ( Figure 1). As we are discussing the effect of genetic modifiers on monogenic disorders, it is essential to clarify why the disease is still referred to as monogenic while multiple variants are involved.…”

“…WGS analysis offers a more comprehensive view of the genome than genotyping array by giving access to almost all of the genetic variants that are present in an individual (coding and non-coding regions). Thus, the exploration of the individual genetic variation is not restricted to single nucleotide variants (SNVs), as it allows the identification of structural variants (SVs) as well [2,19,107,108]. Moreover, continuous improvements in knowledge of the transcriptome, known interactions within and between different biological entities, related ontologies, and bioinformatics tools are providing a better understanding and more precise annotation of the variant effects.…”

“…Although we know very little about Mendelian rare disease modifiers, it is evident that phenotypic variability resulting from modifiers is an important aspect to be considered and researched [16][17][18][19]. For example, as discovered almost one and a half centuries ago (1882), Gaucher disease (GD), one of the rare Mendelian disorders resulting from mutations in the GBA1 gene, is known to have a wide spectrum of phenotypes even among siblings.…”